Behavior supports the stage on which the interplay between the environment and the genome guides evolution. Behavioral adaptations to environmental cues determine survival and reproductive success. Among those environmental cues none are more important than chemical signals. Indeed, odor-guided behavior is essential for most organisms for food localization, avoidance of environmental toxins or predators, oviposition site selection, kin recognition, species recognition and mate selection, and reproduction. The long-term objective of this research program is to obtain a complete description of the genetic architecture that shapes odor-guided behavior in Drosophila melanogaster. This requires identification of all the genes that contribute to olfactory behavior, characterization of genetic interactions among them, and identification of polylmorphisms that generate phenotypic variation in nature. The avoidance response to a repellent odorant, benzaldehyde, serves as a simple and convenient model for odor-guided behavior. Elimination of genetic variance by using controlled genetic backgrounds together with a rapid and quantitative behavioral assay that enables accumulation of large data sets through repeated measurements provides enough statistical power to reproducibly resolve not only large phenotypic effects, but also small smell impairments. The previous funding period achieved characterization of several previously identified smell-impaired (smi) genes at the molecular level. Extended screens identified an additional 79 candidate smi genes. Furthermore, recombination mapping, using a population of recombinant inbred lines, resulted in the discovery of a new highly polymorphic gene, Vanaso that contributes to sex specific phenotypic variation in olfactory behavior. The experiments proposed in this application build on the foundation established during the previous funding period. The specific aims of this proposal are: 1- To characterize a set of new smi genes in greater molecular detail; 2A - To identify gone products that are up-regulated or down-regulated in co-isogenic smi lines of Drosophila melanogaster as a consequence of P-element insertions at smi loci through the use of high density oligonucleotide microarrays; 2B - To quantitatively assess the contributions to odor-guided behavior of new candidate smi genes identified in Specific Aim 2A; 3 - To organize smi genes in epistatic networks; and, 4 -To perform association studies to identify polymorphisms in Va, also and three odorant receptor genes that may contribute to phenotypic variation in olfactory avoidance response to benzaldehyde in natural populations. The completion of these specific aims will lead to a greater, more comprehensive understanding of the genetic architecture of olfactory behavior. [unreadable] [unreadable]